A simulation study of the standard design, the rolling six design, the CRM, and the modified CRM in Phase I clinical trials

The Phase I clinical trial is considered the "first in human" study in medical research to examine the toxicity of a new agent. It determines the maximum tolerable dose (MTD) of a new agent, i.e., the highest dose in which toxicity is still acceptable. Several phase I clinical trial designs have been proposed in the past 30 years. The well known standard method, so called the 3+3 design, is widely accepted by clinicians since it is the easiest to implement and it does not need a statistical calculation. Continual reassessment method (CRM), a design uses Bayesian method, has been rising in popularity in the last two decades. Several variants of the CRM design have also been suggested in numerous statistical literatures. Rolling six is a new method introduced in pediatric oncology in 2008, which claims to shorten the trial duration as compared to the 3+3 design. The goal of the present research was to simulate clinical trials and compare these phase I clinical trial designs. Patient population was created by discrete event simulation (DES) method. The characteristics of the patients were generated by several distributions with the parameters derived from a historical phase I clinical trial data review. Patients were then selected and enrolled in clinical trials, each of which uses the 3+3 design, the rolling six, or the CRM design. Five scenarios of dose-toxicity relationship were used to compare the performance of the phase I clinical trial designs. One thousand trials were simulated per phase I clinical trial design per dose-toxicity scenario. The results showed the rolling six design was not superior to the 3+3 design in terms of trial duration. The time to trial completion was comparable between the rolling six and the 3+3 design. However, they both shorten the duration as compared to the two CRM designs. Both CRMs were superior to the 3+3 design and the rolling six in accuracy of MTD estimation. The 3+3 design and rolling six tended to assign more patients to undesired lower dose levels. The toxicities were slightly greater in the CRMs.^

Optimization of a DNSH passive sampling method to measure airborne carbonyls

Various airborne aldehydes and ketones (i.e., airborne carbonyls) present in outdoor, indoor, and personal air pose a risk to human health at present environmental concentrations. To date, there is no adequate, simple-to-use sampler for monitoring carbonyls at parts per billion concentrations in personal air. The Passive Aldehydes and Ketones Sampler (PAKS) originally developed for this purpose has been found to be unreliable in a number of relatively recent field studies. The PAKS method uses dansylhydrazine, DNSH, as the derivatization agent to produce aldehyde derivatives that are analyzed by HPLC with fluorescence detection. The reasons for the poor performance of the PAKS are not known but it is hypothesized that the chemical derivatization conditions and reaction kinetics combined with a relatively low sampling rate may play a role. This study evaluated the effect of absorption and emission wavelengths, pH of the DNSH coating solution, extraction solvent, and time post-extraction for the yield and stability of formaldehyde, acetaldehyde, and acrolein DNSH derivatives. The results suggest that the optimum conditions for the analysis of DNSHydrazones are the following. The excitation and emission wavelengths for HPLC analysis should be at 250nm and 500nm, respectively. The optimal pH of the coating solution appears to be pH 2 because it improves the formation of di-derivatized acrolein DNSHydrazones without affecting the response of the derivatives of the formaldehyde and acetaldehyde derivatives. Acetonitrile is the preferable extraction solvent while the optimal time to analyze the aldehyde derivatives is 72 hours post-extraction. ^